WO2000002455A1 - Hypericin and hypericum extract: specific t-type calcium channel blocker, and their use as t-type calcium channel targeted therapeutics - Google Patents
Hypericin and hypericum extract: specific t-type calcium channel blocker, and their use as t-type calcium channel targeted therapeutics Download PDFInfo
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Definitions
- Hypericin and Hypericum extract Specific T-type calcium channel blocker, and their use as T-type calcium channel targeted therapeutics
- This invention relates to Hypericum perforatum, extracts of Hypericum perforatum, compounds found in Hypericum perforatum, e.g. hypericin, and the derivatives and analogs of hypericin.
- One aspect of the present invention is the discovery that Hypericum perforatum (referred to as Hypericum herein after unless otherwise indicated), Hypericum extracts, certain compounds in Hypericum, including hypericin, pseudohypericin, hyperforin, ashyperforin, quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, hypericin derivatives and hypericin analogs can be used as therapeutics targeted at T-type calcium channels in various biological systems, such as cardiovascular system, central nervous system and endocrine system, to treat diseases treatable with T-type calcium blocking agents.
- T-type calcium blocking agents include depression, chronic heart failure, congestive heart failure, ischaemc condition, arrhythmia, angina pectoris, hypertension, hypo- and hyperinsulinemia, diabete mellitus, hyperaldosteronemia, epilepsy, migraine headache, brain aging or neurodegenerative related diseases, such as Alzheimer's disease, and preterm labor.
- Hypericin is one of the chemical constituents from a perennial herbaceous plant, Hypericum perforatum or St. John's Wort. Hypericum is known to have medicinal properties since ancient times and it is widely used in phytotheraphy. Hypericum has been widely researched for its antidepressant and anti-viral properties. In addition to these properties, Hypericum has historically been used for a variety of neurological conditions, including anxiety, insomnia due to restlessness, irritability, neuralgia, trigeminal neuralgia, neuroses, migraine headaches, fibrositis, dyspepsia, and sciatica. Hypericum contains several compounds of biological interest, including naphthodianthrones, e.g.
- hypericin and pseudohypericin phloroglucinols, e.g. hyperforin and ashyperforin, and a broad spectrum of flavonoids which are considered to be primarily responsible for Hypericum's activity.
- phloroglucinols e.g. hyperforin and ashyperforin
- flavonoids which are considered to be primarily responsible for Hypericum's activity.
- the lack of a clearly definable pharmacologic mechanism of Hypericum and its chemical components cause the failure of identifying the constituents most responsible for Hypericum's activity.
- Hypericum is effective in treating mild depression. Animal studies also showed that Hypericum extract relieved depressant symptoms. It was reported that Hypericum extract resulted in a down-regulation of adrenergic receptors in the rat frontal cortex after subchronic treatment. Some reported that hypericin inhibited monoamine oxidase (MAO) activity in vitro, but others have failed to confirm this effect. Other proposed mechanisms involve effects on serotonin. At very high doses, Hypericum extract inhibited seretonin re-uptake although it is not known which chemical in the extract is responsible. Studies have shown that both hypericin and pseudohypericin inhibited a variety of virus.
- MAO monoamine oxidase
- Hypericin has been reported to inhibit the growth of glioma cell lines in vitro and to be a potent inducer of glioma cell death due to inhibition of protein kinase C(PKC).
- PKC protein kinase C
- Receptor tyrosine kinase activity of epidermal growth factor has also been reported to be inhibited by hypericin.
- T-type channels are involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing.
- Mibefradil a selective T-channel blocker, induces peripheral and coranary vasodilation. There is no reflex sympathetic activation and no negative inotropic effect. It increases coronary blood flow without increasing oxygen consumption and causes a slight slowing of the heart rate, thereby inducing diastolic relaxation.
- T-type calcium channels also facilitate insulin secretion by enhancing the general excitability of these cells. Therefore, T-type calcium channels may be therapeutic targets in hypo- and hyperinsulinemia (A. Bhattacharjee et al., Endocrinology, vol. 138(9), pp. 3735-40, 1997). A direct link between T-type calcium channel activity and steroidogenesis has been suggested (M.F. Rossier et al., 1996).
- T-type calcium channel blockers such as Hypericum, Hypericum extracts, Hypericum constituents, including hypericin, pseudohypericin, hyperforin, ashyperforin, quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, hypericin derivatives and hypericin analogs of the present invention are effective in treating disorders characterized by an insufficiency of a steroid hormone.
- Hypericum, Hypericum extracts, extracts of species of the Hypericum genus other than Hypericum perforatum, extracts of other plants containing hypericin, constituents of Hypericum, including hypericin, hypericin derivatives and hypericin analogs according to the present invention are expected to be useful for treating T-calcium channel targeted diseases such as arrthymia, coronary diseases, angina, hypertension, migraine, diabetes and preterm labor, etc.
- Hypericum Within the scope of the present invention are processes of using Hypericum; Hypericum extracts; Hypericum constituents, including hypericin, pseudohypericin, hyperforin, ashyperforin, quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin; hypericin derivatives; or hypericin analogs to treat health disorders related to T-type calcium channels or treatable with T-calcium channel blockers in animals, including humans.
- the health disorders related to T-type calcium channels or treatable with T-type calcium blocking agents include depression, chronic heart failure, congestive heart failure, ischaemc condition, arrhythmia, angina pectoris, hypertension, hypo- and hyperinsulinemia, diabete mellitus, hyperaldosteronemia, epilepsy, migraine headache, brain aging or neurodegenerative related diseases, such as Alzheimer's disease, and preterm labor.
- Figure 1 shows the effect of hypericin on L-type calcium current activity in cultured N1 E-115 cells. At doses of 0.1 , 1 and 10 uM, hypericin causes a slight but not significant increase in L-type calcium currents.
- Figure 2 Shows the effect of nifedipine on L-type calcium current activity in cultured N1 E-115 cells. The cells were added into nifedipine after not responding to hypericin (10uM). 1 uM of nifedipine significantly inhibited the currents, indicating the existence of L-type calcium channels.
- Figure 3 shows the effect of hypericin on T-type calcium current in
- Hypericin causes a dose-dependent inhibitory effect on T-type calcium current from 0.1 to 10 uM.
- Figure 4 shows the effect of solvent control for hypericin on T-type calcium channel activity. Since hypericin is dissolved in a solvent of ethanol (50%)+DMSO (50%). This solvent is tested for its ef ect on T-type current. In the amount equivalent to dissolving 0.1 to 10 uM of hypericin, this control solvent does not affect T-type calcium currents.
- FIG. 5 shows the effect of Hypericum extract on T-type calcium current.
- Hypericum extract contains about 0.3% of hypericin and is dissolved in external solution. At 50ug/ml, Hypericum extract significantly inhibited
- Figure 6 shows the effect of hypericin on L-type calcium current in vascular smooth muscle cells.
- Figure 7 shows the effect of hypericin on L-type calcium current in ventricular cells from baby rats.
- Hypericum extract containing the primary compounds, such as hypericin, pseudohypericin, flavonol glycosides, and phloroglucinols, etc, and pure hypericin inhibited T-type calcium channel activity in cultured neuroblastoma cells.
- Hypericum extracts can be obtained either through commercially available sources or extracted from original whole fresh or dried
- Hypericum plant containing not less than 0.04% naphthodianthrones of the hypericin group calculated as hypericin.
- Hypericum extracts can be easily prepared by organic solvent extraction or supercritical fluid extraction by carbon dioxide (E. Bombardelli and P. Morazzoni, Fitowear, vol. 66, pp.
- alkyl alcohols other than ethanol, acetone, methyl n- butyl ketone, n-hexane, DMSO and toluene can be used to extract Hypericum perforatum to make Hypericum extracts.
- the plant, Hypericum perforatum can be obtained worldwide such as England, China, Holland, French, German, Italy, Russia, Spain and Sweden.
- Another embodiment of the present invention includes extracts from species of the Hypericum genus other than St. John's Wort or Hypericum perforatum, and extracts from other plants containing hypericin, as well as methods of using these extracts in treating health disorders related to T- type calcium channels or treatable with T-calcium channel blockers. Also within the scope of the present invention are methods of using species of the Hypericum genus, other than St. John's Wort ⁇ Hypericum perforatum), or other plants containing hypericin to treat health disorders related to T- type calcium channels or treatable with T-calcium channel blockers.
- Hypericum extracts usually contain hypericin and various amounts of other chemicals, including pseudohypericin; a broad range of flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin; phloroglucinols, such as hyperforin and ashyperforin; the essential oil; and xanthones.
- Hypericum constituents include hypericin, pseudohypericin, flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, phloroglucinols, such as hyperforin and ashyperforin, the essential oil from Hypericum perforatum, and xanthones.
- flavonoids such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin
- phloroglucinols such as hyperforin and ashyperforin, the essential oil from Hypericum perforatum, and xanthones.
- Hypericum extract constituents which include hypericin, pseudohypericin, flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, phloroglucinols, such as hyperforin and ashyperforin, the essential oil from Hypericum perforatum, and xanthones.
- methods of using Hypericum constituents or Hypericum extract constituents in treating health disorders related to T-type calcium channels or treatable with T-calcium channel blockers include hypericin derivatives and hypericin analogs.
- Hypercum extract may potentiate the biological effect of hypericin as proved by their synergistic effects of inhibiting T-type calcium channel activity. Also within the scope of the present invention are methods of using hypericin derivatives or hypericin analogs in treating health disorders related to T-type calcium channels or treatable with T-calcium channel blockers.
- hypericin analog refers to compounds having a chemical structure similar to hypericin and having T-type calcium channel blocking activities like hypericin, but “hypericin analog” excludes Mibefradil.
- hypericin analogs include emodin and a compound of formula I shown below.
- hypericin derivatives are compounds modified from hypericin. Pseudohypericin can be considered as a hypericin derivative. Hyperin and hypericin derivatives of the present invention include compounds of formula II shown below.
- R is H, OH, OR or OCOR;
- R 2 is H, R, F, Cl, Br, I or SO 3 H;
- R 3 is H, R, OH, OR, OCOR, CH 2 OH, CH 2 OR, CH 2 OCOR, COOH or COOR;
- R 4 is H, R, OH, OR, OCOR, CH 2 OH, CH 2 OR, CH 2 OCOR, COOH or COOR;
- R 5 is H, R, F, Cl, Br, I or SO 3 H;
- R 6 is H, OH, OR or OCOR
- R 7 is H, OH, OR or OCOR
- R 8 is H, R, F, Cl, Br, I or SO 3 H
- R 9 is H, R, OH, OR, OCOR, CH 2 OH, CH 2 OR, CH 2 OCOR, COOH or COOR;
- R 10 is H, R, OH, OR, OCOR, CH 2 OH, CH 2 OR, CH 2 OCOR, COOH or COOR;
- R Pain is H, R, F, Cl, Br, I or SO 3 H
- R 12 is H, OH, OR or OCOR
- R is an alkyl or substituted alkyl group.
- alkyl represents a C C 30 linear or branched saturated or unsaturated hydrocarbyl group.
- alkyl is a C ⁇ Ce linear or branched saturated or unsaturated hydrocarbyl group.
- the alkyl group of R can be optionally substituted with one to three substituents independently selected from hydroxy, alkoxy, acyloxy, carboxy, akoxycarbonyl, amino, alkylamino, dialkylamino, nitro or phenyl group or fluorine, chlorine, bromine or iodine atom.
- R 2 s H or R R 3 s H, OH, OR, OCOR, CH 2 OH, CH 2 OR or CH 2 OCOR; R 4 s H, OH, OR, OCOR, CH 2 OH, CH 2 OR or CH 2 OCOR; R 5 s H or R; R 6 s H, OH, OR or OCOR; R 7 s H, OH, OR or OCOR; R 8 s H or R; R 9 s H, OH, OR, OCOR, CH 2 OH, CH 2 OR or CH 2 OCOR; R 10 is H, OH, OR, OCOR, CH 2 OH, CH 2 OR or CH 2 OCOR; R restroom is H or R;
- R 12 is H, OH, OR or OCOR; and R is an optionally substituted C r C 6 alkyl group, as well as methods of using these compounds to treat health disorders treatable with T- calcium channel blockers.
- R is an optionally substituted methyl or ethyl group.
- the hypericin derivatives of the present invention with alkyl or substituted alkyl group(s), i.e. compounds of formula II with alkyl or substituted alkyl group(s) at R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , and/or R position can be synthesized from appropriately substituted emodin anthones by dimerization (see Y. Mazur et al, CA 2,029,993; H. Falk et al, Monatsh. Chem., vol. 126, pp. 993-1000, 1995; H. Falk and T.N.H.
- a hypericin derivative wherein R 1f R 3 , R 4 , R 6 , R 7 , and R 12 are OH, R 2 , R 5 , R 8 , and R ⁇ are H, and R 9 and R 10 are C 19 H 39 , was synthesized from anthone of formula I by dimerization in the presence of pyridine N-oxide, piperidine, and ferrous sulfate in pyridine.
- O-Substituted hypericin derivatives or hypericin analogs can be synthesized by direct etherification and esterification of the phenolic hydroxyl group of hypericin and/or hypericin analogs (see H. Falk and T.N.H. Tran, Monatsh. Chem., vol. 127, pp. 717-723, 1996;
- a hypericin derivative wherein R.,, R 3 , R 4 , R 6 , R 7 , and R 12 are OMe, R 2 , R 5 , R 8 , and R lake are H, and R g and R 10 are methyl, was prepared by methylation of hypericin with dimethyl sulfate under basic condition.
- Hypericin derivatives having halogen or sulfonate substitution i.e. compounds of formula II wherein R 2 , R 5 , R 8 , and/or R lake are halogen or SO3H, or halogenated or suifonated hypericin analogs can be synthesized by direct halogenation or sulfonation of hypericin or hypericin analog (H. Falk and W. Schmitzberger, Monatsh. Chem., vol. 124, pp. 77-81 , 1993; H. Falk et al, Monatsh. Chem., vol. 129, pp. 309-318, 1998).
- hypericin derivatives of formula II can be prepared by derivatization of hypericin, pseudohypericin or the hypericin derivatives described above using processes known in the art. For instance, one or more of the hydroxy groups in hypericin, pseudohypericin or the hypericin derivatives described above can be derivatized by converting the hydroxy group(s) to a protected hydroxy group(s) according to the processes described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1991 , the disclosure of which is incorporated by reference.
- hypericin derivatives can be prepared by converting hypericin or pseudohypericin into a prodrug of hypericin or pseudohypericin using processes known in the art, e.g. the processes described in H. Bundgaard, Design of Prodrugs, Elsevier Science Publishers, Amsterdam, 1985, the disclosure of which is incorporated by reference.
- the present invention includes prodrug forms of the agents disclosed above and methods of using the prodrug forms to treat health disorders related to T-type calcium channels or treatable with T-calcium channel blockers.
- hypericin prodrugs, pseudohypericin prodrugs and methods of using hypericin prodrugs or pseudohypericin prodrugs to treat health disorders related to T-type calcium channels or treatable with T-calcium channel blockers are also contemplated in the present invention.
- the present invention also provides pharmaceutical compositions comprising Hypericum, Hypericum extract, or a compound found in Hypericum, i.e. Hypericum constituent, including hypericin, pseudohypericin, hyperforin, ashyperforin, quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, hypericin derivatives or hypericin analogs, admixed with a pharmaceutically acceptable carrier. Also within the scope of the present invention is a pharmaceutical composition comprising at least two Hypericum constituents, one of which is preferably hypericin, with or without a pharmaceutically acceptable carrier. It is further preferred that the pharmaceutical composition comprises hypericin and pseudohypericin. It is also preferred that the pharmaceutical composition comprises hypericin and hyperforin.
- a further aspect of the present invention is a pharmaceutical composition comprising a Hypericum constituent and a hypericin derivative or hypericin analog.
- hypericin and pseudohypericin are naturally occurring pigments and characteristic markers for Hypericum plant and can be extracted in methanol or ethanol.
- Hypericin and pseudohypericin can also be obtained synthetically by processes known in the art. Synthetic hypericin is also available commercially.
- Hypericum extract constituents such as hypericin, pseudohypericin, flavonoids, phloroglucinols and xanthones, can be obtained by synthetic processes known in the art or by high pressure liquid chromatography of Hypericum extracts, followed by work-up procedures known to one skilled in the art.
- the present invention also provides methods of using Hypericum; Hypericum extracts; Hypericum constituents, e.g. hypericin, pseudohypericin, flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, phloroglucinols, such as hyperforin and ashyperforin, the essential oil from Hypericum perforatum, and xanthones; hypericin derivatives; hypericin analogs; or the pharmaceutical compositions disclosed above for treating health disorders related to T-type calcium channels or treatable with T-calcium channel blocksers.
- Hypericum constituents e.g. hypericin, pseudohypericin, flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, phloroglucinols, such as hyperforin and as
- Hypericum, Hypericum extract, hypericin, pseudohypericin, flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, phloroglucinols, such as hyperforin and ashyperforin, the essential oil from Hypericum perforatum, xanthones, hypericin derivatives, hypericin analogs, or the pharmaceutical compositions disclosed above may be administered to an animal, e.g. a mammal such as a human, in need of such a treatment by a parenteral, opthalmological, topical, oral or rectal route or by inhalation.
- parenteral route examples are intravenous, subcutaneous and intramuscular routes.
- Hypericum extract, hypericin, pseudohypericin, flavonoids, such as quercetin, quercitrin, isoquercitrin, hyperoside, rutin, amentoflavone and hyperin, phloroglucinols, such as hyperforin and ashyperforin, the essential oil from Hypericum perforatum, and xanthones, hypericin derivatives, or hypericin analogs may be formulated for parenteral, ophthalmological, topical, oral or rectal administration by compounding these active agents with a conventional vehicle, excipient, binder, preservative, stabilizer, dye, flavoring agent, or the like, as called for by accepted pharmaceutical practice.
- Daily doses are in the range of 0.05 to 500 mg per kg of body weight, prefereably 0.5 to 50 mg per kg of body weight, for Hypericum extract, an extract of a species of the genus Hypericum other than Hypericum perforatum, or an extract of a plant containing hypericin.
- Daily doses are in the range of 0.0001 to 10 mg per kg of body weight, preferably 0.0015 to 0.15 mg per kg of body weight, for hypericin and 0.001 to 5 mg per kg of body weight for a hypericin derivative, such as pseudohypericin, or hypericin analog.
- the daily doses are in the range of 0.01 to 100 mg per kg of body weight, preferably of 0.05 to 50 mg per kg of body weight.
- Hypericum perforatum can be used in the methods of treating health disorders related to T-type calcium channels or treatable with T-calcium channel blockers.
- fresh Hypericum perforatum includes the entire plant of Hypericum perforatum or a portion of Hypericum perforatum plant in a fresh state.
- dried Hypericum perforatum includes the entire plant of Hypericum perforatum or a portion of Hypericum perforatum plant in a dry state, as well as powder resulting from grinding a dried Hypericum perforatum plant or a dried portion of a Hypericum perforatum plant.
- the methods of treatment of the present invention can be performed by administering fresh Hypericum perforatum or dried Hypericum perforatum.
- the daily doses are in the range of 1 to
- the daily doses range from 0.5 to 2000 mg per kg of body weight.
- the actual dose of the active agent used in the method of the present invention to treat a particular subject can be selected from the "daily doses" disclosed above depending on the T-calcium channel activity of the active agent, i.e. Hypericum perforatum, Hypericum extracts, Hypericum constituents, hypericin derivatives or hypericine analogs, used in the treatment, the age, race, sex, species and health condition of the subject to be treated and the type and severity of the health disorder to be treated.
- the above active agents can be administered at the daily doses disclosed above for no more than one day. If needed, the above active agents can be administered to the subject being treated at the above daily doses repetitively day after day.
- the extract or hypericin can also be combined with drugs or any other natural substances known to be effective for treating the condition in question.
- Example 1 Effect of hypericin on L-type calcium current activity in cultured neuroblastoma cells.
- Mouse neuroblastoma cells (N1 E115) were cultured in Dulbecco's modified Eagle's medium (GIBCO) containing 10% fetal bovine serum at 37°C in a humidified atmosphere of 5% CO 2 in air. The medium was changed every 3-4 days. After mechanical agitation, 3 x 104 cells were replanted in 35 mm tissue culture dishes containing 4 ml of bath solution. After cell attachment, the dish was mounted on the stage of an inverted phase-contrast microscope (Nikon) for Ca 2+ channel current recording. These cells expressed predominately T channel currents.
- GIBCO Dulbecco's modified Eagle's medium
- fetal bovine serum fetal bovine serum
- 3 x 104 cells were replanted in 35 mm tissue culture dishes containing 4 ml of bath solution. After cell attachment, the dish was mounted on the stage of an inverted phase-contrast microscope (Nikon) for Ca 2+ channel current recording. These cells expressed predominately T
- Ba 2+ currents through Ca 2+ channels were elicited by 200 msec depolarization at intervals of 5 sec. For every single-cell recording, stable readings were first obtained for 5 min; the drug was then added to the bath solution. Experiments were performed at room temperature(21-22°C) to prolong cell survival and channel recording time.
- the bath solution contained 110 mM Tris, 5 mM KCL, 5 mM CsCL, 20 mM Hepes, 30 mM glucose, 20 mM BaCL 2 , and 0.5 M tetrodotoxin.
- the pipette (internal) solution contained 70 mM Cs 2 -aspartame, EGTA 10, 2 mM ATP-Na 2 , 5 mM K-pyruvate, 5 mM K-succinate, 5 mM Phosphocreatine-Na 2 15 units/ml Creatine kinase, Hepes and 5 mM glucose.
- the osmolarity of all solutions was adjusted to 310-320 mOsm and pH to 7.4 using HCL or CsOH as required.
- Figure 1 shows that hypericin does not significantly affect L-type calcium current.
- Figure 2 shows that Nifedipine, a known L-type calcium channel blocker significantly inhibits L-type calcium currents.
- Example 2 Effect of Hypericin on T-type Calcium Currents in N1 E-115 cells. The method is described as above (Example 1 ). Figure 3 shows that hypericin inhibited T-type calcium currents in a dose-dependent manner. Figure 4 shows that the solvent controls did not affect the T-type calcium currents.
- Hypericum extract is standardized with about 0.3% of hypericin. As shown in Figure 5, at, 50 ug/ml, Hypericum extract containing about 0.15 ug/ml of hypericin significantly inhibited T-type calcium current by more than 60%. However, 0.15 ug/ml of pure hypericin, as shown in Figure 3 produces less than 10% of inhibition on T-type calcium current. This results suggested that the chemicals other than hypericin in Hypericum extract cause a synergistic effect to hypericin on T-type calcium channel activity.
- Example 5 The method is similar to the method described above for Example 1 , except that vascular smooth muscle cells (VSMC) were used. As shown in Fig. 6, hypericin did not affect the L-type calcium current in vascular smooth muscle cells.
- VSMC vascular smooth muscle cells
- the method is similar to the method described above for Example 1 , except that ventricular cells from baby rats were used. As shown in Fig. 7, hypericin did not affect the L-type calcium current in ventricular cells.
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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AU49581/99A AU4958199A (en) | 1998-07-09 | 1999-07-09 | Hypericin and (hypericum) extract: specific t-type calcium channel blocker, and their use as t-type calcium channel targeted therapeutics |
CA2336781A CA2336781C (en) | 1998-07-09 | 1999-07-09 | Hypericin and hypericum extract: specific t-type calcium channel blocker, and their use as t-type calcium channel targeted therapeutics |
JP2000558725A JP2002520260A (en) | 1998-07-09 | 1999-07-09 | Hypericin and hypericum extract: specific T-type calcium channel blockers and their use as therapeutics targeting T-type calcium channels |
KR1020017000390A KR20010071822A (en) | 1998-07-09 | 1999-07-09 | Hypericin and Hypericum Extract : Specific T-type Calcium Channel Blocker, and Their Use as T-type Calcium Channel Targeted Therapeutics |
EP99933542A EP1094712A4 (en) | 1998-07-09 | 1999-07-09 | Hypericin and hypericum extract: specific t-type calcium channel blocker, and their use as t-type calcium channel targeted therapeutics |
US09/481,572 US7195783B2 (en) | 1999-07-09 | 2000-01-11 | Hypericin and hypericum extract: specific T-type calcium channel blocker, and their use as T-type calcium channel targeted therapeutics |
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US9222798P | 1998-07-09 | 1998-07-09 | |
US60/092,227 | 1998-07-09 |
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US09/481,572 Continuation-In-Part US7195783B2 (en) | 1999-07-09 | 2000-01-11 | Hypericin and hypericum extract: specific T-type calcium channel blocker, and their use as T-type calcium channel targeted therapeutics |
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Country Status (7)
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EP (1) | EP1094712A4 (en) |
JP (1) | JP2002520260A (en) |
KR (1) | KR20010071822A (en) |
CN (1) | CN1308492A (en) |
AU (1) | AU4958199A (en) |
CA (1) | CA2336781C (en) |
WO (1) | WO2000002455A1 (en) |
Cited By (12)
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WO2000054760A2 (en) * | 1999-03-15 | 2000-09-21 | Shaman Pharmaceuticals, Inc. | Bicyclo (3.3.1) nonenes useful for the treatment of diabetes and hypertriglyceridemia |
EP1275382A2 (en) * | 1998-11-25 | 2003-01-15 | Universitätsklinikum Freiburg | Hyperforin as cytostatic agent and hyperforin ointment or cream as application form |
EP1284141A2 (en) * | 2001-08-15 | 2003-02-19 | Pfizer Products Inc. | Pharmaceutical combinations comprising neuronal nitric oxide synthase inhibitors for the treatment of neurodegenerative diseases |
WO2003080085A1 (en) * | 2002-03-26 | 2003-10-02 | Lichtwer Pharma Ag | Plant extracts and the use thereof |
EP1553946A2 (en) * | 2002-10-17 | 2005-07-20 | Merck & Co., Inc. | Enhancement of sleep with t-type calcium channel antagonists |
US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
US7166603B2 (en) | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
US7504431B2 (en) | 2004-04-16 | 2009-03-17 | Bristol-Myers Squibb Company | Sulfonyl amide inhibitors of calcium channel function |
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CN103751303A (en) * | 2014-01-18 | 2014-04-30 | 史克勇 | Compound traditional chinese medicine |
US9402848B2 (en) | 2008-02-29 | 2016-08-02 | Vm Therapeutics Llc | Method for treating pain syndrome and other disorders |
CN108084065A (en) * | 2017-11-21 | 2018-05-29 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of hypericin derivative and its preparation method and application |
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CN110025604A (en) * | 2019-04-11 | 2019-07-19 | 中国科学院西北高原生物研究所 | Purposes of the hypericin in the Related product that preparation inhibits glucosidase activity |
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- 1999-07-09 WO PCT/US1999/014132 patent/WO2000002455A1/en not_active Application Discontinuation
- 1999-07-09 CA CA2336781A patent/CA2336781C/en not_active Expired - Lifetime
- 1999-07-09 KR KR1020017000390A patent/KR20010071822A/en not_active Application Discontinuation
- 1999-07-09 AU AU49581/99A patent/AU4958199A/en not_active Abandoned
- 1999-07-09 JP JP2000558725A patent/JP2002520260A/en active Pending
- 1999-07-09 EP EP99933542A patent/EP1094712A4/en not_active Withdrawn
- 1999-07-09 CN CN99808429A patent/CN1308492A/en active Pending
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EP1275382A2 (en) * | 1998-11-25 | 2003-01-15 | Universitätsklinikum Freiburg | Hyperforin as cytostatic agent and hyperforin ointment or cream as application form |
EP1275382A3 (en) * | 1998-11-25 | 2003-02-12 | Universitätsklinikum Freiburg | Hyperforin as cytostatic agent and hyperforin ointment or cream as application form |
WO2000054760A2 (en) * | 1999-03-15 | 2000-09-21 | Shaman Pharmaceuticals, Inc. | Bicyclo (3.3.1) nonenes useful for the treatment of diabetes and hypertriglyceridemia |
WO2000054760A3 (en) * | 1999-03-15 | 2001-03-08 | Shaman Pharmaceuticals Inc | Bicyclo (3.3.1) nonenes useful for the treatment of diabetes and hypertriglyceridemia |
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EP1553946A2 (en) * | 2002-10-17 | 2005-07-20 | Merck & Co., Inc. | Enhancement of sleep with t-type calcium channel antagonists |
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CN108084065B (en) * | 2017-11-21 | 2020-06-16 | 中国农业科学院兰州畜牧与兽药研究所 | Hypericin derivative and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
AU4958199A (en) | 2000-02-01 |
KR20010071822A (en) | 2001-07-31 |
JP2002520260A (en) | 2002-07-09 |
CN1308492A (en) | 2001-08-15 |
CA2336781C (en) | 2010-12-14 |
EP1094712A4 (en) | 2004-09-08 |
EP1094712A1 (en) | 2001-05-02 |
CA2336781A1 (en) | 2000-01-20 |
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